1. Field of the Invention
This invention relates to a locally administrable therapeutic composition for inflammatory eye disease as well as nasal or otic inflammatory disease.
More particularly, it relates to a locally administrable therapeutic composition for inflammatory eye as well as for nasal or otic inflammatory disease, which contains as active ingredient a benzoylphenylacetic acid derivative, a salt thereof or the hydrate of said acid or salt.
The other object of the present invention is to provide a stable locally administrable aqueous composition such as eye drop, otic composition and nasal composition containing the above compounds.
2. Description of the Prior Art
That certain benzoylphenylacetic acid derivatives, when orally administered, exhibit anti-inflammatory activity has been reported in detail in Journal of Medicinal Chemistry, Volume 27, pages 1379-1388 (1984), among others. Furthermore, Japanese Laid Open Patent Publication No. 126124/1987 describes pharmaceutical compositions for percutaneous administration which contain these compounds. However, none of the published literature-inclusive of the above-mentioned patent specification-contains any description indicating or suggesting that these medicinal substances are effective against inflammatory disease of the eye, nose or ear when they are administered topically.
For the treatment, with topical application of drugs, of inflammatory ophthalmopathy such as uveitis and conjunctivitis which are most frequently observed in the ophthalmological field, steroid drugs such as dexamethazone have so far been employed. Topical application of steroid drugs to the eye has some apprehension of increasing intraocular pressure to cause glaucoma. And, there is a fear not only of causing corneal perforation when such steroid drugs are applied to patients suffered from corneal herpes, corneal ulcer or the like, but also of induction of corneal herpes, keratomycosis, Pseudomonas infections and the like by the topical application of steroid drugs. As there has been known such-effects as above, steroid anti-inflammatory agents shall be applied with particular care. In spite of such a situation, there has not been known any non-steroid anti-inflammatory agent compatible with steroid anti-inflammatory drugs in effectiveness for the treatment of inflammatory opthalmopathy such as uveitis. Thus, in the present stage in this technical field, for the treatment of inflammatory ophthalmopathy, it is hardly possible not to use steroid anti-inflammatory agents with particular care to avoid the side effects as above-mentioned. Under such circumstances, it is natural that ophthalmological experts are awaiting the appearance of non-steroid drugs which are effectively usable against uveitis or the like.
The present inventors investigated to find out topically applicable drugs with lesser side-effects and with superior effectiveness by which topically applicable drugs having been employed in the treatment of inflammatory ophthalmopathy, i.e. steroid anti-inflammatory agent, can be replaced. As a result, the present inventors unexpectedly found that certain derivatives of benzoylphenylacetic acid are very effective in the treatment of inflammatory ophthalmopathy, especially of uveitis, by topical application, and that the effectiveness of such drugs is compatible with that of conventional steroid anti-inflammatory drugs.
Furthermore, since the inventors obtained the finding that there are some problems that the above-mentioned benzoylphenylacetic acid derivatives are unstable in an aqueous solution with the optimal pH range for a locally administrable therapeutic composition, they extensively investigated in search of the method for the preparation of a stable aqueous solution. As a result, we have succeeded in preparing a stable aqueous composition. Thus, the stable aqueous composition according to the invention are achieved based on the above finding.
While a number of non-steroid compounds fall under the category of anti-inflammatory agents, all of them are not effective in treating inflammatory eye diseases when topically administered to the eye. This is because there are several problems lying before them. First, when topically administered to the eye, a medicinal agent has to pass through the cornea so that it can reach the site of inflammation. Even when it has succeeded in arriving at the site of inflammation, it must remain there in a necessary concentration for a necessary period of time. If it fails to meet these requirements, it will be unable to produce expected therapeutic effects. Furthermore, in case it is irritative to the eye, it is rather possible that the topical administration of the medicinal agent to the eye would cause exacerbation of symptoms. Therefore, great caution and much care are necessary in selecting a medicinal agent for topical administration to the eye. Furthermore, in case of administration in the form of eye drops, it goes without saying that it is desirable that the eye drop is stable for a long period of time in an aqueous solution without decomposition or forming insoluble matters.
Accordingly, it is an object of the invention to solve the above problems and provide a novel and useful agent for ophthalmic use.
Moreover, the other object of the invention is to provide a sufficiently stable aqueous solution such as eye drops, otic solution and nasal solution which contains the above compounds when stored for a long period of time.